Location

SUMMARY

The long-standing research interest of Nicholas F. LaRusso, M.D., is in hepatic epithelial cell function and dysfunction, with a focus principally on the epithelial cells that line the bile ducts (cholangiocytes) because of their biologic and clinical importance: They constitute the primary target of a group of important diseases of diverse etiologies (cholangiopathies). Dr. LaRusso also works to develop new hypotheses and novel techniques to study cholangiocytes and cholangiopathies.

Dr. LaRusso's research program has had continuous support from the National Institutes of Health for over three decades, including a MERIT Award attesting to the program's relevance.

Focus areas

Cholangiociliopathies. The cholangiociliopathies are a group of incurable genetic diseases characterized by cysts in the liver with or without associated renal cysts. Dr. LaRusso's research team is testing the hypothesis that overexpression of TGR5, a bile acid membrane receptor, in cystic cholangiocytes induces autophagy of discrete miRNAs (miRNAutophagy) via the cyclic adenosine monophosphate (cAMP) signaling pathway, thereby increasing expression of cell cycle proteins and promoting hepatic cystogenesis.

Primary sclerosing cholangitis (PSC). Dr. LaRusso's research team is working to define the mechanisms, consequences and pathologic outcomes of cholangiocyte senescence in the syndrome PSC.

While the cholangiocyte plays an integral role in the cholangiopathies, including PSC, it is not known how cholangiocyte signaling contributes to the initiation and progression of PSC. Dr. LaRusso's team hypothesizes that persistent exogenous insult induces TLR-dependent activation of Ras/MAPK, promoting let-7i miRNA-dependent cholangiocyte senescence and the senescence-associated secretory phenotype (SASP), a phenotype that contributes to the fibroinflammatory features of PSC.

Significance to patient care

Dr. LaRusso's clinical activities are linked to his research program. Indeed, many of the ideas and questions addressed in his lab are direct outgrowths of his interactions with patients. Thus, understanding the pathogenesis of the cholangiopathies facilitates the development of novel therapies targeting key molecules, processes and organelles involved in these diseases.

Research in Dr. LaRusso's lab has already resulted in new and effective pharmacologic treatments for the polycystic liver diseases and is on the verge of breakthrough treatments for other cholangiopathies.

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